RS64668B1 - Montelukast for the treatment of erosive hand osteoarthritis - Google Patents

Description

Description

Technical field

[0001] The present invention relates to the pharmacological control of erosive osteoarthritis of the hand.

State of the art

[0002] Osteoarthritis is a degenerative joint disease that affects the entire joint, including hyaline cartilage, subchondral bone, synovial membrane, ligaments, and joint capsule, and is characterized by articular cartilage degradation, subchondral bone changes, and osteophyte formation at the joint margins, and is usually accompanied by pain. Joints commonly affected by osteoarthritis include the knee, hip and hand.

[0003] Compared to the knee and hip, erosive osteoarthritis of the hand appears to be a distinct, fundamentally different, subgroup of the disease in terms of genetic factors, pathogenesis, and course of the disease, as shown by Ramoneda et al., Joint and bone assessment in hand osteoarthritis, Clin. Rheumatol., 2014, 33 (1), 11-19.

[0004] Also, the article Stern et al., Association of erosive hand osteoarthritis with a single nucleotide polymorphism on the gene encoding interleukin-1 beta, Osteoarthritis Cartilage, 2003, 11 (6), 394-402 confirms that there are genetic factors that are specific for osteoarthritis of the hand and, in particular, for erosive osteoarthritis of the hand, namely, it shows the association between erosive osteoarthritis of the hand and the genomic region containing a polymorphism of one nucleotide interleukin-1b (IL-1b) 5810. Similarly, the article Ramoneda et al., Immunogenic aspects of erosive osteoarthritis of the hand in patients from northern Italy, Scand. J. Rheumatol, 2011, 40, 139-144 also notes some genetic predispositions to erosive osteoarthritis of the hand.

[0005] The specific characteristic of osteoarthritis of the hand is that it simultaneously affects several joints of the hand, which makes it a heterogeneous and complex disorder. However, osteoarthritis of the hand has traditionally received less attention than osteoarthritis of load-bearing joints, such as knees and hips.

[0006] Clinical features of osteoarthritis of the hand include bony enlargements and deformities of the joints of the hand, occasionally accompanied by swelling of soft tissues (Zhang et al., EULAR evidence-based recommendations for the diagnosis of hand osteoarthritis: report of a task force of ESCISIT, Ann. Rheum. Dis., 2009, 68: 8-17). Symptoms of hand osteoarthritis include pain, stiffness, joint deformity, and impaired function, including decreased grip strength, hand mobility, and stiffness, leading to a reduced quality of life for affected patients.

[0007] Erosive osteoarthritis of the hand is a particularly severe form of osteoarthritis of the hand whose predominant features are central erosion and collapse of the subchondral bone plate. Erosive osteoarthritis of the hand can affect the first carpometacarpal (CMC) joint as well as the interphalangeal joints. Erosive osteoarthritis of the hand is characterized by sudden onset, more pronounced pain and impaired function, faster progression, inflammation and worse outcomes than in non-erosive osteoarthritis of the hand.

[0008] Osteoarthritis of the hand is very widespread, with a prevalence of 20–30% in adults, with an increase associated with age, reaching a prevalence of 50% after the age of 60 years, as reported in Gabay et al., Symptomatic Effects of Chondroitin 4 and Chondroitin 6 sulfate on hand osteoarthritis, Arthritis Rheum., 2011, 63 (11), 3383-3391. Among the risk factors for osteoarthritis of the hand, age is perhaps the most significant, with prevalence increasing with age. Furthermore, osteoarthritis of the hand is also gender-related, and is much more prevalent in women than in men, which may indicate a hormonal influence on prevalence. Other common risk factors are obesity, occupational factors, and genetic factors.

[0009] Regarding erosive osteoarthritis of the hand, there is a higher prevalence in women (9.9%) than in men (3.3%) as reported by Haugen et al. Prevalence, incidence and progression of hand osteoarthritis in the general population: the Framingham Osteoarthritis Study, Ann. Rheum. Dis. 2011, 70 (9), 1581-1586. In the population with hand pain or symptomatic hand osteoarthritis, the prevalence of erosive hand osteoarthritis is about 7% and 10%, respectively. However, in the secondary care population with symptomatic hand osteoarthritis, the prevalence rises to 25%.

[0010] Pharmacological treatment of osteoarthritis of the hand, and especially erosive osteoarthritis of the hand, involves specific challenges, which are different from those of osteoarthritis of the hip or knee. Therefore, the primary goal is not only pain management but also essential to improve the functionality of the hand due to the great impact on the quality of life of the affected patients.

[0011] Accordingly, in the 2018 updated version of the EULAR recommendations for the management of osteoarthritis of the hand (Kloppenburg et al., Ann. Rheum. Dis, 2018), it is stated that the primary goal of the management of osteoarthritis of the hand is to control symptoms, such as pain and stiffness, and to optimize function, in order to maximize activity, participation, and quality of life. Patients with osteoarthritis of the hand should not be treated with conventional or disease-modifying biologic antirheumatic drugs, as their efficacy has not been demonstrated.

[0012] Various therapeutic options are presented in the art of managing osteoarthritis of the hand, as shown, for example, in Altman R.D., Pharmacological therapies for osteoarthritis of the hand, Drugs Aging, 2010, 27 (9), 729-745. Current therapeutic options include only analgesics, such as paracetamol, oral nonsteroidal anti-inflammatory drugs (NSAIDs), such as naproxen, dexketoprofen, ibuprofen, or diclofenac, oral opioids, such as tramadol, and oral corticosteroids. However, these drugs can have serious side effects, which typically increase with age, so they may not be recommended for patients with osteoarthritis of the hand.

[0013] Topical treatments, for example, the NSAID diclofenac sodium or capsaicin are preferred in terms of safety, although efficacy may not be completely satisfactory.

[0014] Other drugs reported to relieve pain and improve function in patients with osteoarthritis of the hand are chondroitin sulfate and glucosamine, although there is limited evidence available to support their effectiveness.

[0015] Other treatment options include intra-articular corticosteroids or hyaluronic acid, but they show only modest symptomatic efficacy and it cannot be compared with the efficacy results when these interventions are performed for the treatment of osteoarthritis of the knee or hip.

[0016] In summary, current pharmacological therapy focuses only on symptom relief and the options available so far have shown little efficacy for pain control and often involve unwanted side effects, especially those resulting from the use of oral NSAIDs.

[0017] On the other hand, surgery is not a good option either, because surgical interventions for hand osteoarthritis are much less effective than surgical interventions for knee or hip osteoarthritis.

[0018] Therefore, currently, there is no effective pharmacological therapy for osteoarthritis of the hand and, in particular, for erosive osteoarthritis of the hand, which would either stop the progression of the disease or effectively alleviate its symptoms.

[0019] In the article by Fanning et al., Montelukast sodium as a treatment for experimental osteoarthritis in mice, Osteoarthr. Cartil., 2009, 17 (Suppl. 1), S282, demonstrated the use of montelukast in an experimental model of knee osteoarthritis in mice, where osteoarthritis was surgically induced in the right knees of mice by destabilization of the medial meniscus (DMM). Due to the similarity of the DMM model to humans at risk of osteoarthritis due to meniscal damage, it is suggested that treatment with montelukast may delay the progression of early osteoarthritis in patients nearing the time for meniscal repair. However, nothing has been shown or suggested about the use of montelukast to treat the complexities of erosive osteoarthritis of the human hand, as expected due to the specific genetic factors involved in the onset of erosive osteoarthritis of the hand.

[0020] WO 2015/084883 discloses binding proteins that bind to both IL-1α and IL-1β for use in the treatment of erosive osteoarthritis of the hand.

[0021] Given the high prevalence of erosive osteoarthritis of the hand, the high impact on the quality of life of affected patients and the unsuccessful available therapeutic options, there is a need for new safe and effective pharmacological treatments for the disorder.

Detailed description of the invention

[0022] The object of the present invention is montelukast or a pharmaceutically acceptable salt thereof for use in the treatment of erosive osteoarthritis of the hand in human subjects.

[0023] The authors of the present invention have surprisingly found that montelukast, which is a leukotriene receptor antagonist used to treat asthma and alleviate symptoms of seasonal allergies, is effective for the treatment of osteoarthritis of the hand and, in particular, for the treatment of erosive osteoarthritis of the hand.

[0024] Throughout the specification, as well as in the claims, the terms "one", "some", or "certain" not only include aspects with one element (singular) but also aspects with more than one element (plural).

[0025] The terms "about" or "approximately" referring to amounts, as used herein, are intended to include certain deviations from the qualified amount, namely of ±5%.

[0026] The numerical ranges shown here are intended to include any number that lies within the range and also the upper and lower limits.

Erosive osteoarthritis of the hand

[0027] The present invention relates to the treatment of erosive osteoarthritis of the hand. In the context of the present invention, "treatment" means the treatment of human subjects.

[0028] Patients affected by osteoarthritis of the hand are diagnosed according to standard procedures, which are well known to physicians, either specialists or general practitioners, which typically combine clinical and radiographic observations.

[0029] Osteoarthritis of the hand primarily manifests as pain and swelling of the distal interphalangeal (DIP) joints (Heberden's nodes), proximal interphalangeal (PIP) joints (Bouchard's nodes), and the joints of the base of the thumb; often there is bony enlargement with or without deformity, for example as shown in Arden et al., Atlas of Osteoarthritis, 2014, Springer Healthcare, ISBN 978-1-910315-15-6.

[0030] For example, the ACR (the American College of Rheumatology) criteria are widely followed, as shown in Altman et al. The American College of Rheumatology criteria for the classification of osteoarthritis of the hand, Arthritis Rheum., 1990, 33, 1601-1610. According to those criteria, hand osteoarthritis is diagnosed when there is hand pain, persistent pain, or stiffness, and 3 or 4 of the following: i) hard tissue enlargement of 2 or more joints out of 10 selected joints, ii) hard tissue enlargement of 2 or more distal interphalangeal (DIP) joints, iii) less than 3 swollen metacarpophalangeal (MCP) joints, and iv) deformity of at least 1 of 10 selected joints; with the 10 selected joints being the second and third distal interphalangeal (DIP), second and third proximal interphalangeal (PIP) and first carpometacarpal (CMP) joints of both hands.

[0031] Alternatively, according to the criteria of EULAR (European League Against Rheumatism), as shown in Zhang et al., EULAR evidence-based recommendations for the diagnosis of hand osteoarthritis: report of a task force of ESCISIT, Ann. Rheum. Dis., 2009, 7, 17, a reliable clinical diagnosis of hand osteoarthritis can be made in adults over 40 years of age with (i) pain with use, (ii) intermittent symptoms; and (iii) only mild morning stiffness or stiffness from inactivity affecting one or a few joints at any given time.

[0032] Regarding the radiological assessment, plain radiographs are suitable for the diagnosis of osteoarthritis of the hand, namely, posteroanterior radiographs of both hands. Observed features include joint space narrowing, subchondral bone sclerosis, and subchondral cysts, as is well known in the art.

[0033] Erosive osteoarthritis of the hand is a subgroup of osteoarthritis of the hand characterized by the presence of subchondral bone erosions on the interphalangeal joints on plain radiographs. Typically, erosive osteoarthritis of the hand has an abrupt onset, more rapid progression, and a more aggressive disease course, with marked pain and inflammation and reduced hand functionality. Synovitis and tenosynovitis are also common in erosive osteoarthritis of the hand.

[0034] As shown in Examples 4 and 5, montelukast was surprisingly effective in improving clinical symptoms, relieving pain, improving hand functionality and improving radiological features in patients suffering from erosive osteoarthritis of the hand.

[0035] Furthermore, patients with erosive osteoarthritis of the hand included in those studies were previously treated with conventional therapy with analgesics and/or anti-inflammatory agents and did not respond to such therapy.

[0036] One embodiment of the present invention relates to the treatment of patients suffering from erosive osteoarthritis of the hand that does not respond to treatment with analgesics and/or anti-inflammatory agents.

[0037] As is well known to the ordinary practitioner, patients who do not respond to therapy are those who show no improvement or insufficient improvement in symptoms with therapy.

[0038] In the context of the present invention, the term "treating" or "treating" in relation to osteoarthritis of the hand, and in particular to erosive osteoarthritis of the hand, refers to the elimination, mitigation, improvement or stabilization (i.e. not worsening) of one or more symptoms or manifestations associated with the disease, for example, cartilage degeneration, joint space narrowing, subchondral bone erosion, subchondral sclerosis, osteophyte formation, bone enlargement (for example nodes, such as Heberden's nodes, involving the distal interphalangeal joints and/or Bouchard's nodes, involving the proximal interphalangeal joints), synovitis, tenosynovitis, pain, tenderness, stiffness, inflammation, swelling, reduced grip strength and hand functionality.

[0039] Some of the symptoms are evaluated using radiographic tests, while others are evaluated using clinical assessment such as moderate-severe pain and hand functionality.

[0040] The treatment comprises administering to the subject a therapeutically effective amount of montelukast, a pharmacologically acceptable salt thereof.

[0041] The duration of treatment depends on several factors, mainly on the severity of the condition and its evolution. As it is a degenerative disease associated with old age, chronic administration may be required.

Montelukast

[0042] Montelukast is the International Nonproprietary Name (INN) assigned to the compound 2-[1-[[(1R)-1-[3-[(E)-2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(2-hydroxypropan-2-yl)phenyl]propyl]sulfanylmethyl]cyclopropyl]acetic acid (CAS number: 158966-92-8).

[0043] Pharmacologically, montelukast is a selective antagonist of the cysteinyl leukotriene receptor type 1 (Cys-LT1) used in therapy for the treatment of asthma and allergies. It is commercially available as the sodium salt (montelukast sodium) in medicines to treat asthma and seasonal allergies, for example, sold under the trade name SINGULAIR<®>.

[0044] The preparation of montelukast is shown, for example, in the article Labelle et al., Discovery of MK-0476, a potent and orally active leukotriene D4 receptor antagonist devoid of peroxisomal enzyme induction, Bioorg. Med. Chem. Lett, 1995, 5(3), 283-288. Montelukast is also widely available from commercial sources.

[0045] Chemically, the montelukast molecule includes a carboxylic acid group and is used as the free acid or in the form of its pharmaceutically acceptable salt.

[0046] "Pharmaceutically acceptable" means that said salt is suitable for the preparation of a pharmaceutical composition because it is non-toxic and not biologically undesirable.

[0047] Montelukast, as an acidic compound, can form basic addition salts with organic or inorganic bases. Suitable salt-forming inorganic bases include, but are not limited to, hydroxides of alkali and alkaline earth metals, such as lithium, sodium, potassium, calcium or magnesium hydroxide, to form montelukast lithium, montelukast sodium, montelukast potassium, montelukast calcium or montelukast salts, respectively. Montelukast may also form salts with amines, for example, with ammonia to form montelukast ammonium, or with other organic amines.

[0048] Any pharmaceutically acceptable salt of montelukast is included within the scope of the present invention.

[0049] In a preferred embodiment, montelukast is used as a pharmaceutically acceptable salt.

[0050] In one embodiment of the invention, the pharmaceutically acceptable montelukast salt is selected from alkali metal salts or alkaline earth metal salts, preferably from montelukast lithium, montelukast sodium, montelukast potassium, montelukast calcium or montelukast magnesium, and more preferably montelukast sodium.

[0051] In one preferred embodiment, montelukast is used as montelukast sodium.

[0052] According to the use of the present invention, montelukast can be administered either orally or topically.

[0053] In one embodiment of the invention, montelukast or a pharmaceutically acceptable salt thereof is administered orally.

[0054] When administered orally, montelukast or a pharmaceutically acceptable salt thereof is administered at a dose generally contained in the range of 1-200 mg/day, expressed as montelukast equivalent dose.

[0055] In the clinical study shown in Example 4, oral montelukast at a daily dose of 10 mg was remarkably effective in patients suffering from erosive osteoarthritis of the hand, with relief of pain and improvement in clinical and radiological symptoms.

[0056] Furthermore, in the study shown in Example 5, 9, patients selected from the previous study, who did not respond to treatment with 10 mg of montelukast per day, were given 20 mg of montelukast per day. Surprisingly, it was found that, after only a few days of treatment, the therapy was remarkably effective, both in terms of pain relief and improvement in hand function.

[0057] Montelukast is known as a safe and well-tolerated drug that does not cause side effects even in large doses, for example 200 mg/day (Stroms et al., Clinical safety and tolerability of montelukast, a leukotriene receptor antagonist, in controlled clinical trials in patients aged ≥ 6 years, Clin. Exp. Allergy, 2001, 31, 77-87).

[0058] Therefore, the treatment according to the present invention allows adjusting the dose of montelukast to be given and the duration of the treatment according to the particular condition of each patient and the severity of the disease.

[0059] The preferred oral dose of montelukast is in the range of 2-80 mg/day. A preferred oral dose of montelukast is in the range of 5-70 mg/day. A more preferred oral dose of montelukast is in the range of 10-50 mg/day.

[0060] In one embodiment, the dose of montelukast is in the range of 5-15 mg/day, preferably 7-13 mg/day, more preferably 9-11 mg/day, and even more preferably the dose is about 10 mg/day.

[0061] In one embodiment, the dose of montelukast is in the range of 7-25 mg/day, preferably 10-20 mg/day, more preferably 14-16 mg/day, and even more preferably the dose is about 15 mg/day.

[0062] In one embodiment, the dose of montelukast is in the range of 10-30 mg/day, preferably 15-25 mg/day, more preferably 19-21 mg/day, and even more preferably the dose is about 20 mg/day.

[0063] In one embodiment, the dose of montelukast is in the range of 12-37 mg/day, preferably 20-30 mg/day, more preferably 24-36 mg/day, and even more preferably the dose is about 25 mg/day.

[0064] In one embodiment, the dose of montelukast is in the range of 15-45 mg/day, preferably 25-35 mg/day, more preferably 29-31 mg/day, and even more preferably the dose is about 30 mg/day.

[0065] In one embodiment, the dose of montelukast is in the range of 20-60 mg/day, preferably 35-45 mg/day, more preferably 39-41 mg/day, and even more preferably the dose is about 40 mg/day.

[0066] In one embodiment, the dose of montelukast is in the range of 25-75 mg/day, preferably 45-55 mg/day, more preferably 49-51 mg/day, and even more preferably the dose is about 50 mg/day.

[0067] Suitable oral daily doses of montelukast are, for example, about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 mg. Other higher doses, up to 200 mg/day, are also suitable.

[0068] According to one aspect of the invention, treatment based on montelukast is considered a personalized therapy and is prescribed depending on the patient's reaction to the initial prescribed dose of montelukast and according to the criteria of the specialist.

[0069] The above doses are doses of either montelukast or its pharmaceutically acceptable salts, but are always expressed as an equivalent dose of montelukast.

[0070] Therefore, throughout the subject description, as well as in the patent claims, doses of montelukast are expressed as an equivalent dose of montelukast free acid, regardless of whether it is administered as the free acid or as a salt.

[0071] When montelukast is administered as a salt, the dose is adjusted to provide the required equivalent dose of montelukast free acid.

[0072] Such daily doses may be administered in a single administration, according to a once-daily (q.d.) regimen, or may be divided into several administrations throughout the day, for example, twice daily (b.i.d.), three times daily (t.i.d.) or four times daily (q.i.d.).

[0073] When daily doses of montelukast are administered divided into two or more doses (i.e., b.i.d., t.i.d., or q.i.d.) preferably, the total daily dose is divided into equal partial doses. For example, a dose of 12 mg daily under a regimen of b.i.d. given in two equal doses of about 6 mg; or according to t.i.d. in three equal doses of about 4 mg.

[0074] Preferably, montelukast is administered on a once-daily regimen or twice-daily regimen, and more preferably, montelukast is administered on a once-daily regimen.

[0075] In another embodiment of the invention, montelukast or a pharmaceutically acceptable salt thereof is administered topically.

[0076] Topical administration involves applying an effective amount of montelukast, in the form of a suitable topical pharmaceutical formulation, to the skin of the affected areas of the hand, particularly, near the affected joints.

[0077] Topical administration, as used herein, is equivalent to "transdermal," "transcutaneous," or "percutaneous" administration, and means administration through the skin to deliver montelukast to affected tissues located beneath the skin.

[0078] The dosage of montelukast when administered topically varies depending on the extent and severity of the disease in the affected patient.

[0079] Topical administration is even safer in terms of possible side effects resulting from the systemic absorption of montelukast. Therefore, the dosage in the case of topical administration may be even less limited than in the case of oral administration.

[0080] In topical administration, the dosage may be in the range of 1-200 mg per day per affected hand. Preferably, the dosage range is 2-80 mg, more preferably 5-70 mg and even more preferably 10-50 mg per day per affected hand.

[0081] These dosages can be administered in one single administration per day or divided into several administrations per day.

[0082] The duration of treatment with montelukast, according to the use of the present invention, can vary from about one week to years, depending on the evolution of the disease. Montelukast is a safe drug, essentially free of side effects, and therefore prolonged treatments are suitable, if necessary. An expert doctor will have no difficulty in adjusting the duration of therapy in each particular case, depending on the severity of the disease and the patient's evolution.

Pharmaceutical compositions

[0083] Montelukast or its pharmaceutically acceptable salt according to the use of the present invention is generally administered in the form of a pharmaceutical composition comprising the active ingredient, i.e., montelukast or its pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient and/or carrier.

[0084] Therefore, another aspect of the present invention relates to a pharmaceutical composition comprising montelukast or a pharmaceutically acceptable salt thereof for use in the treatment of erosive osteoarthritis of the hand in a human subject.

[0085] A pharmaceutical composition for use according to the present invention is any conventional formulation that can be prepared by methods well known to one skilled in pharmaceutical formulation, such as those set forth in pharmaceutical technology manuals, for example, in J.P. Remington and A.R. Genaro, Remington The Science and Practice of Pharmacy, 20th edition, Lippincott, Williams & Wilkins, Philadelphia, 2000 [ISBN: 0-683-306472] or in the book M.E. Aulton and K.M.G. Taylor, Aulton's Pharmaceutics, the design and manufacture of medicines, 4th edition, Churchill Livingstone Elsevier, 2013 [ISBN: 978-0-7020-4290-4], or in the book by A.K. Dash, S. Singh and J. Tolman, Pharmaceutics. Basic principles and application to pharmacy practice, Academic Press, Elsevier, 2014 [ISBN: 978-0-12-386890-9].

[0086] Excipients suitable for use in the pharmaceutical compositions of the present invention are also well known to those skilled in pharmaceutical technology and are described, for example, in R.C. Rowe, P.J. Sheskey and P.J. Weller, Handbook of Pharmaceutical Excipients, Sixth Edition, Pharmaceutical Press, 2009.

[0087] Pharmaceutical compositions suitable for use according to the present invention are all those suitable for administration either orally or topically.

[0088] In one embodiment of the invention, the pharmaceutical composition is a composition suitable for oral administration. Any pharmaceutical form suitable for oral administration is included in the use according to the present invention, preferably a solid composition, or else a liquid, in the form of a solution, suspension or syrup, for example.

[0089] Solid dosage forms typically include tablets, capsules, granules and powders.

[0090] Tablets containing montelukast or a pharmaceutically acceptable salt thereof, for use according to the present invention, can be formulated using standard techniques well known in the art. Such tablets may be formulated as conventional compressed tablets, buccal tablets, sublingual tablets, chewable tablets, effervescent tablets, enteric-coated tablets, film-coated tablets, sustained-release tablets, or orally disintegrating tablets by selecting suitable excipients and procedures well known to those skilled in pharmaceutical formulation.

[0091] Alternatively, montelukast or a pharmaceutically acceptable salt thereof may be formulated in capsule form. In capsules, as is well known in the art, the active ingredient, typically with at least one pharmaceutically acceptable excipient, is enclosed in either a hard or soft soluble coating. The main component of the capsule shell is gelatin, while other components include water, colors, pastifiers, such as glycerin or sorbitol, and opacifiers. Alternatively, hypromellose can be used as a capsule coating material.

[0092] The montelukast formulation according to the present invention can also be in the form of powders or granules for oral administration. They may be administered directly into the oral cavity or may be pre-dissolved or dispersed in water or other liquids prior to administration. They can also be effervescent powders or granules.

[0093] Powders are essentially mixtures of dry, finely divided drugs with one or more excipients. Typically, the powders are subjected to a mixing process to obtain a homogeneous mixture, for example by means of trituration, spatula mixing, sieving or tumbling procedures, which are well known in the art.

[0094] Granules consist of powder particles bonded together to form larger particles, and are typically prepared using dry granulation or wet granulation procedures, which are also well known in the art.

[0095] Furthermore, the granules may be coated granules, gastro-resistant granules or modified-release granules.

[0096] Pharmaceutically acceptable excipients that can be used to prepare oral pharmaceutical compositions in solid form, such as tablets, capsules, granules or powders, are well known to those skilled in the art and include, for example, diluents such as calcium carbonate, calcium phosphate, calcium sulfate, cellulose acetate, dextrates, dextrins, dextrose, ethyl cellulose, fructose, gelatin, glyceryl palmitostearate, isomalt, kaolin, lactitol, lactose, magnesium carbonate, magnesium oxide, maltodextrins, maltose, microcrystalline or powdered cellulose, polymethacrylates, pregelatinized starch, starch, sodium carbonate, sodium chloride, sorbitol or sucrose, among others, and mixtures thereof; lubricants, such as calcium stearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, magnesium stearate, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, or talc, among others, and mixtures thereof; disintegrants such as alginic acid, crospovidone, croscarmellose sodium, sodium starch glycolate, starch, low-substituted hydroxypropyl cellulose, among others, and mixtures thereof; binding agents such as acacia, cellulose acetate phthalate, dextrates, dextrin, ethylcellulose, guar gum, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose methylcellulose, maltodextrin, microcrystalline cellulose, sucrose, povidone, pregelatinized starch, sodium carboxymethylcellulose, starch or stearic acid, among others, and mixtures thereof; glidants such as calcium phosphate tobase, powdered cellulose, colloidal silica, magnesium oxide, magnesium silicate, magnesium trisilicate, silica, or talc, among others, and mixtures thereof; sweeteners such as sorbitol, maltitol, mannitol, dextrose, isomalt, maltose, xylitol, saccharin, sucrose, sucralose, aspartame, acesulfame potassium, or trehalose, among others, and mixtures thereof; flavoring agents such as maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, tartaric acid, peppermint, artificial or natural fruit flavors, among others, and mixtures thereof; coloring agents such as curcumin, lactoflavin, iron oxides (red, yellow, or black), caramel, lactoflavin phosphate, cochineal red, titanium dioxide, or carotenes, among others, and mixtures thereof; or mixtures thereof.

[0097] In one embodiment, montelukast or a pharmaceutically acceptable salt thereof for use according to the present invention is in the form of a pharmaceutical composition for oral administration selected from the group consisting of tablets, capsules, powders and granules. In one preferred embodiment, it is in tablet form. In another preferred embodiment, it is in the form of capsules, preferably in the form of hard capsules. In another preferred embodiment, it is in the form of granules. In another preferred embodiment, it is in the form of a powder.

[0098] In one embodiment of the invention, montelukast or its pharmaceutically acceptable salt is used as a powder or granulate composition and is given in the form of monodose sachets, which contain a single dose of the active ingredient. These bags can be made of paper or aluminum or plastic laminates.

[0099] A single dose of montelukast or its pharmaceutically acceptable salt that is contained either in a tablet, or a capsule or a single-dose sachet of a composition in the form of a powder or granules may be a suitable daily dose, when intended for a once-a-day dosing regimen, or may be half a daily dose, when intended for a twice-daily dosing regimen, or may be a third of a daily dose, when intended for a three-times-daily dosing regimen, or may be a quarter of a daily dose, when intended for a dosing regimen dosing four times a day.

[0100] In one embodiment, each tablet, capsule or monodose sachet with powder or granule comprises a dose of montelukast or a pharmaceutically acceptable salt thereof that is contained in the range of 1-200 mg, preferably contained in the range of 2-80 mg, more preferably contained in the range of 5-70 mg, and more preferably contained in the range of 10-50 mg, expressed as an equivalent dose of montelukast. Preferred individual doses may be selected, for example from about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30 mg, expressed as equivalent doses of montelukast when montelukast is used as a salt. Preferred dosages are about 5, about 10, about 15, about 20 mg and about 30 mg of montelukast or an acceptable salt thereof in each tablet, capsule or single dose sachet, expressed as montelukast equivalent dose. These doses are expressed as an equivalent dose of montelukast when montelukast is used as a salt.

[0101] Liquid oral dosage forms of montelukast or a pharmaceutical salt thereof suitable for use according to the present invention include solutions, suspensions or syrups, for example.

[0102] Oral solutions contain the active substance dissolved in a carrier, which is typically water optionally with additional co-solvents. Syrups are oral aqueous solutions that contain high concentrations of sucrose or other sugars. Sugar-free syrups are obtained by replacing sucrose with hydrogenated glucose, mannitol, sorbitol or xylitol, for example. In oral suspensions, the active substance is dispersed in a liquid medium. The oral solution and/or suspension formulation includes one or more additional excipients, such as solubilizers, stabilizers, buffers, antioxidants, preservatives, flavoring agents, coloring agents, and sweeteners, among others.

[0103] The most common carrier in oral solutions and suspensions is water; other suitable co-solvents include ethanol, propylene glycol, polyethylene glycol 300 or 400, and glycerin, among others, and mixtures thereof. As is well known in the art, other suitable adjuvants for use in oral solutions and/or suspensions include buffering agents such as diethanolamine, dibasic sodium phosphate, monobasic sodium phosphate, potassium citrate, sodium bicarbonate, sodium citrate dihydrate, among others, and mixtures thereof; surfactants such as polyoxyethylene castor oil derivatives and sorbitan esters; preservatives such as benzalkonium chloride, benzyl alcohol, bronopol, parabens, sodium benzoate, sodium propionate, sorbic acid, domiphene bromide or thimerosal, among others, and mixtures thereof; antioxidants such as sodium sulfite, sodium bisulfite, sodium metabisulfite, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, and mixtures thereof; viscosity modifiers such as acacia, alginic acid, bentonite, carbomer, carrageenan, gelatin, glycerin, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, maltodextrin, polyvinyl alcohol, sodium alginate, tragacanth, or xanthan gum, among others and mixtures thereof; suspending agents such as xanthan gum, guar gum, alginic acid, bentonite, carbomers, sodium or calcium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl alginate, microcrystalline or powdered cellulose, colloidal anhydrous silica, dextrins, gelatins, kaolin, magnesium aluminum silicate, maltitol, povidone, sorbitan esters, or tragacanth, among others, and their mixtures; flavoring agents such as maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, tartaric acid, peppermint, artificial or natural fruit flavors, among others, and mixtures thereof; sweeteners such as sorbitol, maltitol, mannitol, dextrose, isomalt, maltose, xylitol, saccharin, sucrose, sucralose, aspartame, acesulfame potassium or trehalose, among others, and mixtures thereof; coloring agents such as curcumin, lactoflavin, caramel, lactoflavin phosphate, cochineal red, or carotenes, among others, and mixtures thereof.

[0104] In one embodiment, montelukast or a pharmaceutically acceptable salt thereof for use according to the present invention is in the form of a liquid pharmaceutical composition for oral administration selected from a solution and a suspension.

[0105] Typically, such liquid dosage forms for oral use may be supplied as multi-dose or single-dose preparations. Each dose from the multidose container is administered using a device suitable for measuring the prescribed volume. The measuring device can be, for example, in the form of a spoon, a cup, an oral syringe, or a dropper.

[0106] Each measured dose typically comprises an amount of montelukast or a pharmaceutically acceptable salt thereof contained in the range of 1-200 mg, preferably contained in the range of 2-80 mg, more preferably contained in the range of 5-70 mg, and even more preferably contained in the range of 10-50 mg, expressed as an equivalent dose of montelukast. Preferred individual doses may be selected, for example, from about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30 mg, expressed as equivalent dose of montelukast when montelukast is used as a salt. Preferred doses are about 5, about 10, about 15, about 20 mg and about 30 mg of montelukast or an acceptable salt thereof in each measured dose of the liquid composition, expressed as an equivalent dose of montelukast.

[0107] In another embodiment of the invention, the pharmaceutical composition is suitable for topical administration. Any pharmaceutical form suitable for topical administration is included in the use of the present invention, typically in liquid or semi-solid form. A liquid composition suitable for topical administration may be prepared by dissolving or dispersing montelukast or a pharmaceutically acceptable salt thereof in a suitable vehicle such as, for example, water, alcohols, glycols, or mixtures thereof, such as, for example, lotions, liniments, or tinctures; or that liquid composition can be used to impregnate a carrier in the form of a compress or bandage that is applied to the affected area; or alternatively the liquid composition can be sprayed onto the affected area using a pump sprayer or aerosol.

[0108] Other forms of topical administration are semi-solid compositions such as creams, gels, ointments or pastes, which include a pharmaceutically acceptable carrier or carrier in which montelukast or its pharmaceutically acceptable salt is dissolved, emulsified, dispersed or suspended.

[0109] Creams, as is well known to experts in pharmaceutical technology, are semi-solid emulsions, which can be of the oil-in-water (o/w) or water-in-oil (w/o) type, formulated from an oil phase, an aqueous phase and an emulsifying agent. Gels are obtained from a liquid that has been gelled by adding a rheological or gelling agent. Ointments are semi-solid fatty preparations, which contain the active ingredient in dissolved or dispersed form. Ointments can be formulated with various carriers such as paraffin, plastibazes (a mixture of polyethylene with a series of hydrocarbons) or vegetable oils. Pastes are prepared analogously to fats, and show a firmer consistency since they contain larger amounts of insoluble solids.

[0110] The carrier in the topical composition may be water or other water-soluble or water-miscible carriers, such as lower alcohols (eg, ethanol or isopropanol), glycols (eg, ethylene glycol, propylene glycol, or polyethylene glycol 300), or glycerol, among others, or mixtures thereof. Suitable oil carriers include almond oil, corn oil, sesame oil, castor oil, soybean oil, paraffin oil, peanut oil, olive oil, cottonseed oil, lanolin, glyceryl monostearate, or linseed oil, among others, or mixtures thereof. Additional excipients include emulsifiers such as calcium stearate, stearic acid, cetyl alcohol, ethylene glycol palmitostearate, glyceryl monostearate, lecithin, phospholipids, oleic acid, poloxamers, sodium lauryl sulfate, sorbitan esters, polyoxyethylene castor oil derivatives, or emulsifying wax, among others, and mixtures thereof; gelling agents such as carrageenan, guar gum, tragacanth gum, locust bean gum, xanthan gum, pectin, agar, alginic acid, carbomers, carboxymethylcellulose, methylcellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, and polyethylene glycol, among others, and mixtures thereof; emollients such as petrolatum, mineral oil, myristyl, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, glyceryl monostearate, glyceryl monooleate, isopropyl myristate, isopropyl palmitate, cholesterol, lanolin alcohols, and glycerin, among others, and mixtures thereof; thickening agents or viscosity-increasing agents such as carbomers, sodium carboxymethylcellulose, calcium carboxymethylcellulose, hyaluronic acid, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropylmethyl cellulose, acacia, guar gum, xanthan gum, alginic acid, bentonite, carrageenan, clay, gelatin, sodium alginate, tragacanth, among others and mixtures thereof; antioxidants such as ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, chelating agents, citric acid monohydrate, fumaric acid, malic acid, potassium metabisulfite, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, sodium sulfite, sodium thiosulfate, among others, and combinations thereof; preservatives such as benzalkonium chloride, benzyl alcohol, bronopol, chlorhexidine, imidurea, parabens, phenoxyethanol, sodium benzoate, sodium propionate, sorbic acid or thimerosal, among others, and mixtures thereof; buffering agents and pH adjusting agents, such as boric acid, citric acid monohydrate, diethanolamine, sodium phosphate dibasic, malic acid, maleic acid, sodium phosphate monobasic, potassium citrate, sodium acetate, sodium carbonate, sodium bicarbonate, sodium citrate dihydrate, sodium borate, sodium hydroxide, sodium lactate, triethanolamine, among others, and mixtures thereof; fragrances such as mint, herbal, cocoa butter and floral oil fragrances, among others; and coloring agents suitable for pharmaceutical use; among others, and their mixtures.

[0111] In one embodiment, montelukast or a pharmaceutically acceptable agent thereof for use according to the present invention is in the form of a pharmaceutical composition for a composition for topical administration selected from the group consisting of creams, gels, ointments and pastes.

[0112] The percentage of montelukast or a pharmaceutically acceptable salt thereof in the pharmaceutical composition may vary according to the specific pharmaceutical dosage form and the particular intended dosage. Typically, the percentage of active ingredient in an oral solid pharmaceutical composition is between 0.1 and 50% w/w, expressed as an equivalent amount of montelukast in relation to the total weight of the composition.

[0113] In an oral liquid pharmaceutical composition, the concentration of montelukast or its pharmaceutically acceptable salt can also vary widely depending on the specific formulation and the desired concentration, for example, from 0.1 to 20% w/v, expressed as equivalent grams of montelukast in 100 ml of the composition.

[0114] In topical compositions, the amount of montelukast or its pharmaceutical salt may be in the range of 0.5-50 wt/wt %, for example, expressed as an equivalent amount of montelukast relative to the total weight of the composition.

[0115] Further, some examples are provided for the purpose of illustrating the invention, but not limiting it. The invention is defined by patent claims.

Examples

Example 1. - Preparation of orodispersible powder with montelukast

[0116] The composition in powder form was prepared using the following components in the range of mass concentrations included in the table below:

[0117] All ingredients were placed in a suitable container and mixed in a rotating drum for 10 to 30 minutes. The resulting mixture was placed in monodose bags. Each single-dose sachet contained from 200 mg to 500 mg of the composition.

Example 2. - Preparation of tablets with montelukast

[0118] The tablet composition was prepared using the following components:

[0119] The composition was prepared according to the following procedure: first, all the ingredients forming the core of the tablet were sifted. Then the active ingredients were mixed with the other core components for 30 minutes to achieve homogeneity. Magnesium stearate was then added, and mixing was continued for 5 to 10 minutes. The tablets obtained after the compression process are coated with the coating components during the time required to achieve a suitable coating. Each tablet contained from 200 mg to 500 mg of the composition.

Example 3. - Preparation of a formulation with the consistency of an aqueous gel for topical administration

[0120] The gel composition was prepared using the following components:

[0121] The composition was prepared according to the following procedure: montelukast sodium was dissolved in a mixture composed of purified water, isopropyl alcohol, ethanol, isopropyl myristate and butyl hydroxytoluene. The mixture was subjected to continuous stirring to achieve homogeneity. When the mixture became homogeneous, hydroxyethyl cellulose was added, and the mixture was mixed until the polymer swelled and a homogeneous mixture with the consistency of an aqueous gel was obtained. The fragrance was then added and the pH was adjusted to a suitable value for topical administration (in the range of 5.5–8.0) using hydrochloric acid and sodium hydroxide. Finally, the mixture is mixed until homogeneous.

Example 4. - Clinical study of 10 mg montelukast orally per day in patients with erosive osteoarthritis of the hand

[0122] A preliminary clinical observational study was performed in patients suffering from erosive osteoarthritis of the hand.

[0123] 50 patients with erosive osteoarthritis of the hand who did not respond or had a limited response after treatment with analgesics and/or anti-inflammatory agents were selected for the study. Patients were administered 10 mg of montelukast daily orally, using an orally dispersible composition prepared as shown in Example 1, according to a once-daily dosing regimen.

[0124] The duration of treatment ranged from 3 to 16 months.

[0125] The following parameters were used to evaluate the efficacy of the treatment: (i) improvement in clinical symptoms; (ii) efficacy in pain relief; and (iii) improvement in radiological evaluation. All assessments focused on a handful of patients.

[0126] Improvement in clinical symptoms was assessed by evaluating improvement in symptoms such as functionality, stiffness and deformity of the affected hand, including improvement in patients' quality of life.

[0127] To assess the efficacy in pain relief, patients were asked to evaluate the pain they felt using a visual analog scale (VAS) methodology, both before treatment and at the end of the treatment period. Treatment was considered effective in relieving pain when, on a scale of 0 to 10, a reduction of at least 2 units was observed after treatment.

[0128] To evaluate the effectiveness of the treatment in the radiological parameters of the hand, the following characteristics were evaluated in the affected joints: a) edema, b) subchondral erosions, c) synovitis and d) tenosynovitis. These characteristics were radiologically evaluated using posteroanterior radiographs of the hand, which were taken before and after the treatment period. Treatment was considered to provide radiological improvement if there was a detectable improvement in at least two of the assessed characteristics and if there was no deterioration in the other characteristics.

[0129] After the treatment period, 32 patients showed an obvious improvement in clinical symptoms.

[0130] 45 out of 50 patients reported pain before starting treatment. After the treatment period, 28 of those 45 pain patients reported effective pain relief.

[0131] 28 patients showed improvement after radiological evaluation: 28 showed improvement in synovitis, 18 showed improvement in tenosynovitis, 19 showed improvement in edema, and 14 showed improvement in erosions. The improvement in the assessed radiological features was remarkable in the majority of these patients. Furthermore, 10 additional patients showed no worsening of the assessed radiological parameters.

Example 5 - Clinical study of 20 mg montelukast orally daily in patients with erosive osteoarthritis of the hand

[0132] For that study, 9 patients from the previous study (Example 4) were selected among those who did not respond to treatment (10 mg montelukast daily).

[0133] In the present study, patients were administered a daily dose of montelukast of 20 mg orally, also using an orally dispersible composition prepared as shown in Example 1, according to a once-daily dosing regimen. The age of the patients ranged from 52 to 78 years.

[0134] As in the previous study, to evaluate the effectiveness in alleviating pain, a visual analog scale (VAS) methodology was used, where pain was evaluated on a scale from 0 to 10.

[0135] To evaluate the effectiveness in improving the functionality of the hand, a visual analog scale (VAS) from 0 to 10 was also used, where 0 meant full functionality, i.e., the complete ability to hold an object, and 10 meant the absence of functionality, i.e., the inability to hold any object.

[0136] The following table summarizes the results of the study:

[0137] No treated patients reported any side effects.

[0138] "Initial" values mean values before starting treatment, and "final" values mean values after completing treatment.

[0139] The Min-Max range shows the individual minimum and maximum values established for each evaluated parameter within the patient population.

[0140] In terms of pain, all selected patients suffered from moderate to severe pain before the start of treatment, as a VAS value higher than 4 was generally considered to mean significant pain.

[0141] It was found that the response to 20 mg of montelukast per day was very significant, both in terms of pain relief and in improving the functionality of the hand, as shown in the previous table.

[0142] It was found that there were significant differences in both variables at the beginning and end of treatment (p << 0.0005 in both cases), with a mean decrease in pain of 3.8960.54 and a mean improvement in hand functionality of 4.5660.39. Almost 70% of patients who did not respond to treatment with 10 mg montelukast daily showed a 55% pain relief after receiving 20 mg montelukast daily. All patients showed significant improvement in hand function (35% improvement) after receiving 20 mg montelukast daily.

Example 6. - Efficacy of topical montelukast in patients with erosive osteoarthritis of the hand

[0143] One patient diagnosed with erosive osteoarthritis of the hand who was treated with a topical corticoid, methylprednisolone aceponate, for 12 weeks, once daily, without any improvement in either pain relief (remained with a score higher than 5 on a scale of 0–10 using the VAS methodology) or radiological assessment (showed disease progression during treatment) was included in the study.

[0144] After a washout period of several weeks, the patient began treatment with a topical formulation prepared as shown in Example 3, at a dose of about 10 mg per day per hand, applied to the affected area for a period of 12 weeks. After treatment, the patient showed significant pain relief and improvement in the clinical symptoms of osteoarthritis.

Claims (15)

Patent claims 1. Montelukast or a pharmaceutically acceptable salt thereof for use in the treatment of erosive osteoarthritis of the hand in human subjects. 2. A pharmaceutically acceptable salt of montelukast for use according to claim 1. 3. A pharmaceutically acceptable salt of montelukast for use according to claim 2, characterized in that the pharmaceutically acceptable salt of montelukast is selected from an alkali metal salt or an alkaline earth metal salt, and preferably the salt is montelukast sodium. 4. Montelukast or its pharmaceutically acceptable salt for use according to any one of claims 1 to 3, characterized in that montelukast or its pharmaceutically acceptable salt is for oral administration. 5. Montelukast or its pharmaceutically acceptable salt for use according to claim 4, characterized in that the dose of montelukast or its pharmaceutically acceptable salt is contained between 1 and 200 mg/day, expressed as an equivalent dose of montelukast. 6. Montelukast or its pharmaceutically acceptable salt for use according to claim 5, characterized in that the dose of montelukast or its pharmaceutically acceptable salt is contained between 5 and 15 mg/day, preferably contained between 7 and 13 mg/day, more preferably contained between 9 and 11 mg/day, and even more preferably the dose is about 10 mg/day, expressed as an equivalent dose of montelukast. 7. Montelukast or its pharmaceutically acceptable salt for use according to claim 5, characterized in that the dose of montelukast or its pharmaceutically acceptable salt is contained between 7 and 25 mg/day, preferably contained between 10 and 20 mg/day, more preferably contained between 14 and 16 mg/day, and even more preferably the dose is about 15 mg/day, expressed as an equivalent dose of montelukast. 8. Montelukast or its pharmaceutically acceptable salt for use according to claim 5, characterized in that the dose of montelukast or its pharmaceutically acceptable salt is contained between 10 and 30 mg/day, preferably contained between 15 and 25 mg/day, more preferably 19-21 mg/day, and even more preferably the dose is about 20 mg/day, expressed as an equivalent dose of montelukast. 9. Montelukast or its pharmaceutically acceptable salt for use according to claim 5, characterized in that the dose of montelukast or its pharmaceutically acceptable salt is contained between 15 and 45 mg/day, preferably contained between 25 and 35 mg/day, more preferably contained between 29 and 31 mg/day, and even more preferably the dose is about 30 mg/day, expressed as an equivalent dose of montelukast. 10. Montelukast or its pharmaceutically acceptable salt for use according to any one of claims 1 to 3, characterized in that montelukast or its pharmaceutically acceptable salt is for topical administration. 11. Montelukast or its pharmaceutically acceptable salt for use according to any of claims 1 to 3, characterized in that montelukast or its pharmaceutically acceptable salt is in the form of a pharmaceutical composition comprising montelukast or its pharmaceutically acceptable salt and at least one pharmaceutically acceptable auxiliary agent and/or carrier. 12. Montelukast or its pharmaceutically acceptable salt for use according to claim 11, characterized in that montelukast or its pharmaceutically acceptable salt is in the form of a solid pharmaceutical composition for oral administration selected from the group consisting of tablets, capsules, powders or granules. 13. Montelukast or its pharmaceutically acceptable salt for use according to patent claim 12, characterized in that each monodose bag with tablets, capsules or powder or granules includes a dose of montelukast or its pharmaceutically acceptable salt contained in the range of 1-200 mg, expressed as an equivalent dose of montelukast. 14. Montelukast or its pharmaceutically acceptable salt for use according to claim 11, characterized in that montelukast or its pharmaceutically acceptable salt is in the form of a pharmaceutical composition for topical administration, which is preferably selected from the group consisting of cream, gel, ointment and paste. 15. Montelukast or its pharmaceutically acceptable salt for use according to patent claim 14, characterized in that the amount of montelukast or its pharmaceutically acceptable salt in the composition is in the range of 0.5-50 wt/wt%, expressed as an equivalent amount of montelukast in relation to the total weight of the composition. Published and printed by: Institute for Intellectual Property, Belgrade, Kneginje Ljubice 5